The LIM domain is a cysteine-rich motif which was first defined in the proteins Lin-11 from C. elegans (Freyd, G. et al. (1990) Nature 344:876-879), insulin gene enhancer binding protein ISL1 from rat (Karlsson, O. et al. (1990) Nature 344:879-882), and Mec-3 from C. elegans (Way, J. C. et al. (1988) Cell 54:5-16). The name LIM is derived from the first letter of the names of these three proteins.
The sequence of the LIM domain is highly conserved among proteins found in different tissues and across a variety of species (Sanchez-Garcia, I. et al. (1994) Trends Genet. 10:315-320). Two main classes of LIM proteins are known. One class consists of proteins that, like Lin-11, ISL1 and Mec-3, contain two LIM domains plus a homeodomain and are thus designated LIM-HD proteins. The second class of LIM proteins consists of one or more LIM domains without a homeodomain and are thus designated "LIM-only" proteins.
A LIM domain is defined by a consensus amino acid sequence. (Wang, X. et al. (1992) J. Biol. Chem. 267:9176-9184 The domain contains two adjacent zinc-finger motifs which bind two zinc ions. LIM domains appear to function as protein-binding interfaces (Schmeichel, K. L. et al. (1994) Cell 79:211-219), and they may act as cofactors in cell signaling.
Chromosomal translocations associated with T-cell acute lymphoblastic leukemia (T-ALL) have led to the identification of several potential oncogenes (Rabbitts, T. H. (1991) Cell 67:641-644). Many of the T-ALL associated chromosomal translocations have been localized to the T-cell receptor (TCR) genes. Two genes, rhombotin-1 and -2 (RBTN-1 and -2), are over expressed in cells which carry recurring T-ALL chromosomal translocations (McGuire, E. A. et al. (1989) Mol. Cell. Biol. 9:2124-2132; Boehm, T. et al. (1991a) Proc. Natl. Acad. Sci. USA 88:4367-4371). The RBTN genes are also known as T-cell translocation gene-1 and -2 (TTG-1 and -2).
RBTN1 gene expression is developmentally regulated (Greenberg, J. M. et al. (1990) Nature 344:158-160) and occurs mainly in embryonic and adult brain (Boehm, T. et al. (1991b) Oncogene 6:695-703). RBTN2gene expression is more widespread and occurs in the fetal mouse central nervous system, lung, kidney, liver and spleen (Boehm, et al. 1991b, supra). RBTN2 is essential for normal erythroid cell development in mice, and a homozygous null mutation in RBTN2 results in failure of yolk sac erythropoiesis and embryonic death (Warren, A. J. et al. (1994) Cell 78:45-57). Although they are associated with T-cell tumorigenesis, the RBTN1 and RBTN2 genes are expressed at very low levels in normal T-cells and thymus (Boehm et al., 1991b, supra; Royer-Pokora, B. et al. (1991) Oncogene 6:1887-1993). Transcriptional deregulation of the RBTN genes in T-cells, as a result of chromosomal translocations, may be an important step in T-cell oncogenesis (Royer-Pokora et al., supra).
The oncogenic potential of RBTN1 and RBTN2 in T-cells was confirmed by expression of these proteins in transgenic mice. Mice carrying RBTN1 or RBTN2, directed to express in thymus-derived cells, developed T-cell tumors and acute lymphoblastic lymphomas (Fisch, P. et al. (1992) Oncogene 7:2389-2397; McGuire, E. A. et al. (1992) Mol. Cell Biol. 12:4186-4196). The latency period for lymphoid tumor appearance was variable. No tumors appeared in control mice with a RBTN1 transgene expressed in pancreas by the insulin transcriptional promoter. Fisch et al. suggest that the RBTN genes may contribute to leukemogenesis by affecting T-cell development rather than by inducing proliferation, and that the effect of T-ALL associated chromosomal translocation of the RBTN-1 and RBTN-2 genes may be the equivalent of a preleukemic change that establishes the cells on an irreversible path that may lead to overt leukemia.
The discovery of polynucleotides encoding RBTN-like proteins, and the molecules themselves, provides a means to investigate physiological processes relating to the control of cellular differentiation and proliferation. Discovery of RBTN-like proteins satisfies a need in the art by providing new diagnostic or therapeutic compositions useful in the treatment or prevention of diseases relating to disregulated cell growth and proliferation, including cancer.